Polymorphic forms of ivabradine hydrochloride

Abstract

Stable crystalline Form II and stable crystalline Form III of ivabradine hydrochloride and processes for their preparation are disclosed.

We claim: 
     
       1. A crystalline Form II of ivabradine hydrochloride, wherein the crystalline Form II comprises:
 (i) X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 (ii) a water content from about 2.0% to about 4.0% w/w. 
 
     
     
       2. The crystalline Form II of ivabradine hydrochloride according to  claim 1  further comprising X-ray powder diffraction peaks at about 8.05°, 8.69°, 12.11°, 15.50°, 16.18°, 18.02°, 19.00°, 19.80°, 21.72°, 22.42°, 24.16° , 25.46° and 27.36°±0.2° (2θ). 
     
     
       3. The crystalline Form II of ivabradine hydrochloride according to  claim 1  comprising an endothermic peak in the range of 197° C. - 199 ° C. 
     
     
       4. A process for the preparation of crystalline Form II of ivabradine hydrochloride, wherein the crystalline Form II comprises:
 X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 a water content from about 2.0% to about 4.0% w/w, the process comprising:
 a) providing a solution of ivabradine hydrochloride in one or more solvents by heating at about 30° C. to about 120° C.; 
 b) obtaining the crystalline Form II of ivabradine hydrochloride by the removal of the solvents; and 
 c) drying the crystalline Form-II of ivabradine hydrochloride at about 40° C. to about 70° C., wherein the solvent is at least one member selected from the group consisting of methanol, ethanol, isopropanol, butanol, dimethylformamide, 
 
 dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone ethyl acetate, butyl acetate, isopropyl acetate, 
 acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water and mixtures thereof. 
 
     
     
       5. The process according to  claim 4 , wherein the removal of the solvent comprises one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum. 
     
     
       6. A process for the preparation of crystalline Form II of ivabradine hydrochloride, wherein the crystalline Form II, comprises:
 X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 a water content from about 2.0% to about 4.0% w/w, the process comprising:
 a) contacting ivabradine base with hydrogen chloride in one or more first solvents to get ivabradine hydrochloride; 
 b) obtaining a solution of ivabradine hydrochloride in one or more second solvents; 
 c) optionally adding water to the solution, heating the solution and cooling the solution to obtain the ivabradine hydrochloride wet-cake; and 
 (d) treating the wet-cake with one or more of first solvents to obtain the crystalline Form II of ivabradine hydrochloride, 
 
 wherein the first solvent is at least one member selected from the group consisting of methanol, ethanol, isopropanol, butanol, dimethylformamide, dimethyl acetamide, dimethylsulfoxide, N-methylpyrrolidone, methyl ethyl ketone, acetone, methyl isobutyl ketone, ethyl acetate, butyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water and mixtures thereof. 
 
     
     
       7. The process according to  claim 6 , wherein the second solvent comprises one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water, or mixtures thereof. 
     
     
       8. A process of packaging crystalline Form II of ivabradine hydrochloride comprising;
 (i) X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 (ii) a water content from about 2.0% to about 4.0% w/w, the process comprising:
 a) placing crystalline ivabradine hydrochloride under nitrogen atmosphere in a nonpermeable bag and tying with a thread; 
 b) placing the bag of step (a) inside a black color polyethylene bag, optionally containing oxygen busters and sealing it; 
 c) placing the bag of step (b) inside a triple laminated bag, optionally containing oxygen busters and sealing it; and 
 d) placing the sealed triple laminated bag inside a high density polyethylene (HDPE) container and sealing it. 
 
 
     
     
       9. A pharmaceutical composition comprising a therapeutically effective amount of crystalline Form II of ivabradine hydrochloride, comprising:
 (a) X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 (b) a water content from about 2.0% to about 4.0% together with one or more pharmaceutically acceptable carriers, excipients, or diluents. 
 
     
     
       10. A crystalline Form II of ivabradine hydrochloride comprising
 (a) X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 (b) a water content from about 2.0% to about 4.0% w/w, having particle size distributions wherein the 10 th  volume percentile particle size (D10) is less than about 50 μm, the 50th volume percentile particle size (D50) is less than about 200 μm, or the 90 th  volume percentile particle size (D90) is less than about 400 μm, or any combination thereof. 
 
     
     
       11. The crystalline Form II of ivabradine hydrochloride according to  claim 1 , comprising:
 (a) X-ray powder diffraction peaks at about 15.50°, 18.02°, 19.00°, 19.80°, 22.42°, 24.16°, and 25.46°±0.2° (2θ); and 
 (b) a water content from about 2.0% to 4.0% w/w wherein the crystalline Form II of ivabradine hydrochloride is stable after exposure to a relative humidity of 75% at 40° C. or 60% at 25° C. for a period of at least six months and is substantially free from known crystalline forms or an amorphous form.